SUMMARY Chemistry and Pharmacology of Iboga Alkaloids Ibogaine is the major psychoactive alkaloid of Tabernanthe iboga, a shrub native to West Central Africa. Since the 1960?s, ibogaine has been known for its ability to interrupt drug addiction. In light of the growing drug use and drug overdose epidemics in the U.S., there is an urgent need for new therapeutics to treat opioid use disorder (OUD) and other substance use disorders (SUDs) - and ibogaine represents an important prototype in this direction. Two recent observational clinical studies confirmed the earlier reports of ibogaine?s effects that include a rapid and long-lasting relief of opioid withdrawal symptoms and cravings, and an increased rate and duration of abstinence in opioid-dependent subjects. The observed response size was comparable to that of methadone replacement therapy. These clinical observations have been replicated in preclinical rodent models of SUDs, including attenuation of self-administration of opioids, cocaine, alcohol and nicotine, mitigation of naloxone-precipitated withdrawal symptoms, and reversal of analgesic tolerance in opioid-dependent animals. The current mechanistic model for ibogaine invokes a role for several key molecular targets, including the a3b4 nicotinic receptor, kappa opioid receptor (KOR), and monoamine transporters. An active metabolite, noribogaine, also makes a significant contribution to the pharmacological effects of ibogaine. We have developed new synthetic methods for de novo synthesis of the iboga alkaloid scaffold, which unlocks unlimited exploration of its pharmacology. We have found that substitution of the indole amine group with other heteroatoms enables accentuation of specific mechanisms of the noribogaine pharmacological profile. The proposed research will focus on benzofuran analogs of noribogaine (oxa-noribogaine) that represent a new class of KOR modulators. Our preliminary results have shown that oxa-noribogaine induces a potent analgesia with no sedative/dissociative side effects in mice, and complete and long-lasting suppression of morphine self- administration in rats, providing a strong rationale for the proposed research. In this application, we will explore the oxa-iboga system in terms of synthetic methods, KOR and opioid receptor pharmacology and signaling, off-target pharmacology, in vivo target validation, and efficacy examination in rat models of OUD. We will also explore the central hypothesis that the benzofuran iboga analogs exhibit an atypical KOR modulator profile that underlies the favorable separation of analgesia and side effects, as well as the efficacy in OUD models. We have assembled an interdisciplinary team with significant experience in synthetic chemistry, computational design, opioid receptor signaling, mouse behavior, and SUD preclinical pharmacology.